Prevalence of Sleep Disturbances in Children With Neurofibromatosis Type 1

Licis, Amy; Vallorani, Alicia; Gao, Feng; Chen, Cynthia; Lenox, Jason; Yamada, Kelvin A.; Duntley, Stephen P.; Gutmann, David H.

doi:10.1177/0883073813500849

Cited by 60 publications

(44 citation statements)

References 37 publications

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“…Analysis of REM sleep showed small differences in overall bout distribution between genotypes, with more 30–60 s REM bouts sleep in Nf1 CKO mice (Figure i). Taken together, the finding of increased sleep fragmentation parallels the sleep deficit (lack of sleep maintenance) observed in patients with NF1 (Licis et al., ) and suggests that this model could be employed to discern the molecular basis for this defect in mammals. For example, in other experimental systems, sleep fragmentation induces cognitive deficits by regulating NADPH oxidase (Nair et al., ), as well as negatively impacting spatial learning and synaptic plasticity (Wallace et al., ), raising the intriguing possibility that sleep fragmentation in patients with NF1 could exacerbate their coexisting learning and memory problems.…”

Section: Resultsmentioning

confidence: 75%

“…Although there was no difference in the average percentage of theta power between genotypes (4–8.5 Hz; data not shown), Nf1 CKO mice exhibited increased delta power (1–4 Hz) compared with controls, both in awake (Figure a) and in NREM sleep (Figure b), but not during REM sleep (Figure c) over 24 hr of recording. The increased delta power in Nf1 CKO mice could signify hypersomnolence in Nf1 CKO mice, in contrast to patients who lack excessive somnolence (Licis et al., ). Alternatively, increased delta power is often interpreted as reflecting slower overall background EEG activity, which can also influence global cognitive function (Astill, Van Der Heijden, Van Ijzendoorn, & Van Someren, ), further compounding the comorbid learning and attention deficits found in people with NF1 (Knyazev, ).…”

Section: Resultsmentioning

confidence: 99%

“…Sleep disorders are commonly reported in patients with the neurofibromatosis type 1 (NF1) neurogenetic syndrome caused by germline mutations in the NF1 gene. In these studies, parasomnias, difficulties initiating sleep, early morning awakenings and excessive sleep/wake transitions were most frequently described in children and adults with NF1 (Leschziner, Golding, & Ferner, ; Licis et al., ). Of these sleep‐related problems, difficulties with sleep initiation and maintenance, as well as sleep/wake transitions, predominated in both men and women with NF1.…”

Section: Introductionmentioning

confidence: 99%

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Neurofibromatosis type 1 (Nf1)‐mutant mice exhibit increased sleep fragmentation

Anastasaki

Rensing

Johnson

et al. 2019

Journal of Sleep Research

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Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder in which affected children and adults are at a higher risk of sleep disorders. In an effort to identify potential sleep disturbances in a small animal model, we used a previously reported Nf1 conditional knockout (Nf1CKO) mouse strain. In contrast to Nf1 mutant flies, the distribution of vigilance states was intact in Nf1CKO mice. However, Nf1CKO mice exhibited increased non‐REM sleep (NREM)‐to‐wake and wake‐to‐NREM transitions. This sleep disruption was accompanied by decreased bout durations during awake and NREM sleep states under both light and dark conditions. Moreover, Nf1CKO mice have higher percentage delta power during awake and NREM sleep states under all light conditions. Taken together, Nf1CKO mice phenocopy some of the sleep disturbances observed in NF1 patients and provide a tractable platform to explore the molecular mechanisms governing sleep abnormalities in NF1.

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Section: Resultsmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neurofibromatosis type 1 (Nf1)‐mutant mice exhibit increased sleep fragmentation

Anastasaki

Rensing

Johnson

et al. 2019

Journal of Sleep Research

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“…In contrast, our 78-year-old patient presented with fl attening of the paraventricular gyri and reduction of brain parenchyma with hypodensity of the white matter in terms of cortical atrophy; periventricular bilateral small post-ischemic microvascular lesions of varying chronicity. Other, uncommon but wellknown neurological complications include headaches, sleep disorders, epilepsy, cerebral edema, mental retardation and tumors of the spinal cord and brain (22,23).…”

Section: Discussionmentioning

confidence: 99%

Extensive Peculiar Cutaneous Form of Neurofibromatosis Type I as a New Mutation - a Case Report

Balaban

Popović

2016

Serbian Journal of Dermatology and Venereology

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Neurofi bromatosis-1 (NF1) is one of the most common hereditary multisystemic disorders. The disease manifests a variety of characteristic features that include: hyperpigmentary abnormalities of the skin (café-au-lait macules, freckles in the axillae, and iris Lisch nodules) and growth of benign peripheral nerve sheath tumors (neurofi bromas) in the skin. Associated extracutaneous clinical features include: skeletal abnormalities, neurological, cardiovascular, endocrine and other malformations. NF1 is caused by mutation in the neurofi bromatosis-1 gene, which codes for the protein neurofi bromin. The inheritance of NF1 follows an autosomal dominant trait, although about 50% of patients present with new ("de novo") mutations, and represent the fi rst member of their family. No difference in the severity of the disease can be found in patients with familial mutations versus those with new mutations. We present a 78-year-old female patient with an extreme cutaneous form of neurofi bromatosis who reported no affected family member. Apart from skin problems, she had no major health issues in childhood and adolescence, but in recent decades she had frequent headaches, occasional abdominal pain, and vision and hearing impairment. About 10 to 14 days before admission, she developed a severe cough, shortness of breath, and chest and abdominal pain. On examination, the patient of short stature (hight: 152 cm, weight: 49 kg) presented with thousands of soft nodules dispersed over the whole body, except on extensor sides of thighs and lower legs; the nodules varied in color from skin-colored, livid erythematous, to brown-grey; the nodules on the abdomen were moist, partly bleeding from the base, and accompanied by an unpleasant odor. Her feet were also densely covered by dark purple lumps, with dystrophic changes of the toe nails that were thickened, frayed, and yellowish. The skeletal abnormalities included: short stature, severe osteoporosis and osteosclerosis of the head bone structure; degenerative arthropathc-spondylotic changes of the thoracolumbar spine segment with signs of diffuse skeletal hyperostosis; pronounced degenerative changes of the lumbar spine. CT scans of the head, chest and abdomen showed the following abnormalities: fl attening of the paraventricular gyri and reduction of brain parenchyma with hypodensity of the white matter in terms of cortical atrophy; periventricular bilateral small post-ischemic microvascular brain lesions of varying chronicity; in the parenchyma of the upper left lung lobe the apical presence of small areas of pleural effusion with consequent subatelectic region; distended stomach and a small inner wall herniation; hypotrophic right kidney; atherosclerotic lesions of the abdominal aorta; low grade infrarenal kinking of the abdominal aorta. Pathohistological analysis of biopsy specimen taken from the nodule corresponded with cutaneous neurofi broma. Consultative examinations of various specialists pointed to the existence of the following comorbidities: obstructive respira...

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“…A possibly related behavioral phenotype is impaired sleep. Pediatric patients have problems with initiating and maintaining sleep, arousal, sleep-wake transition and hyperhidrosis [6][7][8]. This aspect of NF1 has not been studied extensively either in humans or in model systems.…”

Section: Introductionmentioning

confidence: 99%

Genetic inhibition of Anaplastic Lymphoma Kinase rescues cognitive impairments in Neurofibromatosis 1 mutant mice

Weiss

Weber

Torres

et al. 2017

Behavioural Brain Research

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Heterozygous Neurofibromatosis 1 (NF1) loss of function mutations occur in approximately 90% of patients with neurofibromatosis. A major, disabling phenotypic consequence of reduced NF1 function is cognitive impairment; a possibly related behavioral phenotype is impaired sleep. Recent results in Drosophila have demonstrated a genetic interaction between Anaplastic Lymphoma Kinase (Alk) and NF1 for both associative learning and sleep. Inhibition of Alk improves associative learning and sleep in heterozygous NF1 mutant flies. The results in Drosophila provide a strong motivation to investigate NF1/Alk genetic interactions in mice. In Drosophila, activation of Alk by its ligand, Jelly belly (Jeb), is the physiologically relevant target of negative regulation by NF1. Therefore, we tested whether genetic inhibition of Alk in heterozygous NF1 mutant mice attenuates or rescues cognitive impairments in mice. Our results are consistent with the hypothesis that NF1 functions in mice biochemically to inhibit signaling from Alk through Ras. The cognitive phenotypes observed in heterozygous NF1 mutant mice are rescued or ameliorated by genetic inhibition of Alk activity. In two tests of hippocampus-dependent learning, the Morris water maze and extinction of contextual fear, mutation of one or both alleles of Alk was sufficient to improve performance to wild type or near wild type levels in NF1-/+ mice. In addition, in NF1 mice genetic inhibition of Alk improves circadian activity levels. These data are intriguing in light of the circadian alterations seen in NF1 patients and indicate that inhibition of Alk activity may cognitively benefit patients with Neurofibromatosis 1.

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Prevalence of Sleep Disturbances in Children With Neurofibromatosis Type 1

Cited by 60 publications

References 37 publications

Neurofibromatosis type 1 (Nf1)‐mutant mice exhibit increased sleep fragmentation

Neurofibromatosis type 1 (Nf1)‐mutant mice exhibit increased sleep fragmentation

Extensive Peculiar Cutaneous Form of Neurofibromatosis Type I as a New Mutation - a Case Report

Genetic inhibition of Anaplastic Lymphoma Kinase rescues cognitive impairments in Neurofibromatosis 1 mutant mice

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